Amino acids are often employed as raw materials in the preparation, by a sequence of reactions, of compounds having various uses. In many of these sequences as for example peptide synthesis, it is necessary to reversibly block an amino or imino group of a salt of the amino acid in order that the blocked compound may undergo further reactions which would otherwise irrevocably destroy the amino or imino group, and yet permit later regeneration of the amino or imino group.
The benzyloxycarbonyl group (also known as the carbobenzoxy group or the (phenylmethoxy)carbonyl group) has been extensively used for this purpose. The benzyloxycarbonyl group may be introduced by reacting a salt of the amino acid with a benzyl haloformate such a benzyl chloroformate or benzyl bromoformate. The blocked amino acid salt may then be reacted to form reaction products in which the amino or imino group remains blocked. In most cases, it is eventually desired to remove the benzyloxycarbonyl group and regenerate the amino or imino group. However, the benzyloxycarbonyl group is not easily removed under mild conditions. Consequently, hydrogenation is customarily used for this purpose. Hydrogenation is not a desirable reaction to carry out since it employs hydrogen which is extremely flammable and since it usually employs a catalyst such as palladium on carbon or Raney nickel. A further disadvantage of the hydrogenation process is that toluene is left in the reaction mixture as a contaminant.
Use of the tertiary-butoxycarbonyl group (also known as the 1,1-dimethylethoxycarbonyl group) possesses several advantages over use of the benzyloxycarbonyl group as the blocking group. One such advantage is that the tertiary-butoxycarbonyl group may be removed and the amino or imino group regenerated by treatment with strong acid to a pH of about 1 or less under mild temperature conditions. Another advantage is that the by-products of the tertiary-butoxycarbonyl group upon removal are isobutene (viz., 2-methylpropene) and carbon dioxide, which are both gasses and therefore easily removed from the reaction mixture. The principal disadvantages center on introduction of the tertiary-butoxycarbonyl group. Di-tertiary-butyl dicarbonate, ##STR1## has been used for this purpose, but the compound is very expensive and contributes only one tertiary-butoxycarbonyl group for blocking purposes; and remaining portion of the molecule reacts to form carbon dioxide and either tertiary-butanol or isobutene. Another group of compounds, the unsubstituted or ring-substituted tertiary-butyl phenyl carbonates, have also been employed but a byproduct of the reaction is the corresponding phenol which is difficult to remove from the reaction mixture. Yet other compounds that have been employed include tertiary-butoxycarbonylazide, tertiary-butoxycarbonylfluoride, 1-tertiary-butoxycarbonyl-1,2,4-triazole, and 1-tertiary-butoxycarbonyl-3-methylimidazolium salts.
Klee and Brenner, Helvetica Chimica Acta, volume 44, pages 2151-2153, disclosed reacting sodium glycinate and 1-(tertiary-butoxycarbonyl)imidazole in a sealed tube for 15 hours at 110.degree. C. to produce, after acidification, N-(tertiary-butoxycarbonyl)glycine in 46 percent yield. Similarly, N-(tertiary-butoxycarbonyl)-DL-phenylalanine was obtained in 25 percent yield. These yields are low and the conditions unsuitable for commercially viable processes. Indeed, Bram, Tetrahedron Letters No. 6, pages 469-472, indicates that 1-(tertiary-butoxycarbonyl)imidazole is stable but only slightly reactive with respect to the amine compounds.